Glucocorticoids (also known as anti-inflammatory corticosteroids, corticosteroids, or simply as "steroids" in the ophthalmic literature) have been known since the early 1950's as effective therapeutic agents for reducing ocular inflammation. The introduction of anti-inflammatory steroid therapy, using a variety of local and systemic routes of delivery, continues to provide a means to decrease the inflammation which otherwise would damage and impair the vision of the patient. Ophthalmic steroid therapy proved useful to a wide variety of inflammatory and irritating conditions in the eye where other therapies either did not work as well or were ineffective. Steroids were not useful for many other conditions, especially chronic ones in which inflammatory mechanisms did not play a clear pathogenic role (including cataract, most forms of glaucoma, and macular degeneration).
As ophthalmic steroid therapy became more widespread, and more potent and stable steroids became available, it became clear that their use involved a number of potential side-effects, one of the first of which noticed was elevation of pressure within the eye (intraocular pressure [IOP]). Concern over this side-effect has become a limitation on the long-term ophthalmic use of both potent and less active steroids, especially because a number of cases were reported in which irreversible blindness has occurred due to unrecognized increased IOP.
When detailed evaluations of the potent ophthalmic steroid formulations was conducted in large populations using standardized testing protocols (four times a day administration of ophthalmic 0.1% dexamethasone eyedrops), it was determined that elevated IOP occurred relatively frequently in the general population within three to six weeks. Potentially serious elevations in IOP occurred in some patients within the first week of ophthalmic steroid administration. The longer the duration and the more frequent the steroid administration, the more likely a given patient was shown to develop elevated IOP. Approximately 5 percent of the general population show an accentuated IOP elevation to topical ophthalmic steroids (in which IOP can increase from its normal 10 to 20 mm Hg to over 35 mm Hg) occurring in the one-to-six week time frame of steroid administration. Some patients who did not show a nigh response to the normal steroid eyedrop testing protocol did show a large IOP rise with longer treatments and/or different routes (e.g. injectable steroids) of steroid administration. If undetected, such high elevations of IOP (as well as elevations in the range of 20 to 30 mm Hg) were known to put the patient at substantial risk of glaucomatous damage as evidenced by loss of vision in visual field testing and optic nerve damage. Even minor increases in IOP can be detrimental in some patients such as those with low-tension glaucoma.
Elevated IOP is currently recognized as an important risk factor for the development of optic nerve damage and visual field loss in otherwise normal individuals. The concern is even greater for patients who are already demonstrating such damage due to glaucoma. Individuals with primary open-angle glaucoma (POAG), also called "chronic glaucoma", which is the most prevalent type of glaucoma, have additional problems with ophthalmic steroid therapy in that these patients (and their genetically related family members) appear predisposed to high IOP elevations due to steroids. Patients with pigmentary glaucoma also appear to have an increased sensitivity to steroid administration, while other forms of glaucoma do not appear to have this increased sensitivity.
In addition to direct ophthalmic steroid use, dermatologic steroids used on the face and eyelids are sufficient to produce elevated IOP and visual loss in some individuals. Elevated IOP occurs also with systemic steroid use, increased endogenous steroids as occurs with Cushing's Syndrome, and POAG itself may involve an increased activity or response to excessive endogenous glucocorticoid activity.
Efforts have been made to substitute non-steroidal anti-inflammatory (NSAI) agents, from the group of drugs known as cyclooxygenase inhibitors (a number of which were known useful in treating systemic inflammatory medical conditions), for the use of steroids in the treatment of ocular inflammation and ocular pain syndromes. These agents have not shown the same propensity to produce side-effects in ocular tissues as do ophthalmic steroids (in addition to the IOP rise, steroid side effects include steroid cataract, delayed wound healing, and the masking or spreading of infections), although a concern has remained that NSAI agents might elevate IOP or produce other steroid-related complications in the eye since their accepted mechanism of action is to inhibit the production of prostaglandins and other eicosanoids similar to steroids. Because prostaglandin administration does appear to decrease IOP and to increase outflow, blockage of endogenous prostagladins by steroid (or NSAI agents) in trabecular meshwork cells from the aqueous outflow pathway could contribute to a rise in IOP. See, e.g., Weinreb et al., Arachidonic Acid Metabolism in HTM Cells, Investigative Ophthalmology & Visual Science, Vol. 29, No. 11 (1988) and Weinreb et al., Prostaglandin Production by HTM Cells: In Vitro Inhibition by Dexamethasone, Investigative Ophthalmology & Visual Science, Vol. 24, No. 12 (1983).
Doulakas (U.S. Pat. No. 4,829,088) discloses the use of an ophthalmic medicament containing diclofenac-sodium in aqueous solution for the treatment of inflammations of the eye. Diclofenac-sodium is a non-steroidal anti-inflammatory agent which is said to be a suitable alternative for the treatment of severe acute or chronically recurrent inflammatory symptoms in the eye. The aqueous solution is made suitable for the local treatment of inflammations of the eye due to its stability against chemical decomposition of the diclofenac-sodium and preservation properties and toleration by the eye.
Nagy (U.S. Pat. No. 4,960,799) also discloses aqueous ophthalmic solutions containing diclofenac-sodium. The solutions, having a pH of about 7.0 to about 7.8, comprise per milliliter of solution about 0.1 to about 5.0 milligrams of (a) pharmaceutically acceptable salt of ortho-(2,6-dichlophenyl-)aminophenyl acetic acid; (b) about 0.1 to about 10 milligrams of a pharmaceutically acceptable salt of ethylene diamine tetraacetic acid, (c) about 0.5 to about 200 milligrams of a pharmaceutically acceptable solubilizer, (d) about 0.01 to about 5.0 milligrams of a pharmaceutically acceptable bacteriostat and (e) the remainder water. The ophthalmic solutions are used for topical administration to the eye for the control or treatment of ocular inflammation.
Cherng-Chyi et al. (U.S. Pat. No. 5,110,493) relates to ophthalmic non-steroidal anti-inflammatory drug formulations containing a quaternary ammonium preservative and a non-ionic surfactant. The formulations are useful for treating diseases that are either caused by, associated with or accompanied by inflammatory processes.
The NSAI agents used in the eye have been tested empirically for different ocular inflammatory conditions, using drugs that had been selected previously in systemic studies for their ability to suppress prostaglandin production and to decrease inflammatory responses in animals and humans. In the eye, these NSAI agents appear to provide at least some benefit to prevent particular side-effects of surgical trauma, fluid accumulating in the back of the eye, appearance of inflammatory cells and vessel leakage in the anterior chamber, and the presence of pain. Although potentially useful to these conditions and ocular disease states, and some ocular conditions such as post surgical macular edema appear to respond better to some NSAIs than steroid administration, NSAI agents do not appear as fully-effective alternatives for steroid treatment of ocular inflammation in many other conditions, and in a variety of individual clinical settings ophthalmic steroid therapy is still preferred.
As mentioned earlier, steroids (glucocorticoids) are believed to alleviate inflammation at least in part by inhibiting the production of prostaglandins and other eicosanoids at early stage involving the utilization of arachidonic acid (by interactions with lipomodulin-like molecules), although it is clear that other steroid actions also contribute to their antiinflammatory effects. NSAIs also are believed to inhibit the formation of prostaglandins and other eicosanoids at a later step (by interaction with the enzyme cyclooxygenase) as the major mechanism for their antiinflammatory effects. However, since steroids and NSAI agents both effectively inhibit prostaglandin and other eicosanoid pathways, a concern has been that both classes of drugs might elevate IOP.